Nicotine-containing pharmaceutical compositions

ABSTRACT

A composition intended to be employed for therapeutic purposes incorporates nicotine and at least one other nicotinic compound. Representative forms of nicotine can be as a free base (e.g., as a mixture of nicotine and microcrystalline cellulose), as a form of nicotine salt (e.g., as nicotine bitartrate) or as nicotine polacrilex. The other nicotinic compound is a compound that can be considered to bind selectively to certain nicotinic receptor subtypes, and particularly those of the central nervous system. For example, the other nicotinic compound can be a compound that binds selectively to the nicotinic receptor subtypes α 7  or α 4 β 2 . The composition is useful for treatment of central nervous system conditions, diseases and disorders, and as a nicotine replacement therapy.

FIELD OF THE INVENTION

The present invention relates to compositions that contain nicotine, andin particular, to nicotine-containing pharmaceutical compositionsintended to be administered to provide a pharmacological effect, orotherwise used for therapeutic purposes.

BACKGROUND

Central nervous system (CNS) conditions, diseases, or disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. They comprise neuropsychiatricdisorders, neurological diseases and mental illnesses; and includeneurodegenerative diseases, behavioral disorders, cognitive disordersand cognitive affective disorders. The clinical manifestations ofseveral CNS conditions, diseases or disorders have been attributed toCNS dysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors).

Nicotinic compounds, such as nicotine, are capable of affectingnicotinic acetylcholinergic receptors (nAChRs). Subtypes of nAChRs existin both the CNS and the peripheral nervous system (PNS), but thedistribution of subtypes is heterogeneous. For instance, certainsubtypes which are predominant in vertebrate brain, others predominateat the autonomic ganglia, and others predominate at neuromuscularjunction. Activation of nAChRs by nicotinic compounds results inneurotransmitter release. See, for example, Dwoskin et al., Exp. Opin.Ther. Patents, 10: 1561-1581 (2000); Schmitt et al., Annual Reports inMed. Chem., 35: 41-51 (2000); Huang et al., J. Am. Chem. Soc., 127:14401-14414 (2006); Arneric et al., Biochem. Pharmacol., 74: 1092-1101(2007) and Millar, Biochem. Pharmacol., 78: 766-776 (2009), which areincorporated herein by reference.

It has been suggested that administration of nicotine, and othernicotinic compounds, can result in various pharmacological effects. See,for example, U.S. Pat. Nos. 5,583,140 to Bencherif et al.; 5,723,477 toMcDonald et al.; 7,001,900 to Jacobsen et al.; 7,135,484 to Dart et al.and 7,214,686 to Bencherif et al.; and US Pat. Pub. No. 2010/0004451 toAhmad et al., which are incorporated herein by reference. As a result,it has been suggested that nicotine, and other nicotinic compounds, canexhibit utility in the treatment of a wide variety of conditions,diseases, and disorders, including those that affect the CNS.Additionally, administration of nicotine and nicotinic compounds hasbeen proposed for treatment of certain other conditions, diseases, anddisorders. See, for example, U.S. Pat. Nos. 5,604,231 to Smith et al.;5,811,442 to Bencherif et al.; 6,238,689 to Rhodes et al.; and 6,489,349to Bencherif et al., which are incorporated herein by reference.Furthermore, administration of nicotine has been employed in an effortto help cigarette smokers quit smoking (i.e., as a smoking cessationaid). For example, nicotine has been an active ingredient of varioustypes of so-called “nicotine replacement therapy” or “NRT” products.

It has been proposed to administer nicotine using a transdermal patch.Representative types of nicotine-containing transdermal patch productshave been marketed under the tradenames “Habitrol,” “Nicoderm,”“Nicorette,” “Nicorette CQ,” “Nicotinell” and “ProStep.” See also, forexample, U.S. Pat. Nos. 4,597,961 to Etscom; 5,298,257 to Bannon et al.;5,603,947 to Wong et al.; 5,834,011 to Rose et al.; 6,165,497 to Osborneet al.; and 6,676,959 to Anderson et al., which are incorporated hereinby reference. It also has been suggested that transdermal administrationof nicotine can be accompanied by ingestion of other types ofnicotine-containing products. See, for example, U.S. Pat. No. 5,593,684to Baker et al.; US Pat. Pub. No. 2009/0004249 to Gonda; and Fagerstrom,Health Values, 18:15 (1994), which are incorporated herein by reference.

One particularly popular way to provide for oral administration ofnicotine has been through the use of nicotine-containing gum.Nicotine-containing gum products have been marketed under the tradenames“Nicorette,” “Nicotinell” and “Zonnic.” See also, for example, U.S. Pat.Nos. 3,845,217 to Ferno et al.; 3,877,468 to Lichtneckert et al.;3,901,248 to Lichtneckert et al.; 6,344,222 to Cherukuri et al.;6,358,060 to Pinney et al.; 6,773,716 to Ream et al.; and 6,893,654 toPinney et al.; and US Pat. Pub. No. 2004/0191322 to Hansson, which areincorporated herein by reference.

Another way that has been employed to provide oral administration ofnicotine has been through the use of nicotine-containing lozenge ortablet types of products. Nicotine-containing lozenge, mini lozenge,tablet, and microtab types of products have been marketed under thetradenames “Commit,” “Nicorette,” “Nicotinell” and “NiQuitin.” See also,for example, U.S. Pat. Nos. 5,110,605 to Acharya; 5,733,574 to Dam;6,280,761 to Santus; 6,676,959 to Andersson et al.; and 6,248,760 toWilhelmsen; US Pat. Pub. Nos. 2001/0016593 to Wilhelmsen and2010/0004294 to Axelsson et al., which are incorporated herein byreference.

Nicotine also has been administered in the form of nasal or oral sprays.Various exemplary ways to administer nicotine in the form of a nasalspray are set forth in U.S. Pat. Nos. 4,579,858 to Ferno et al.;5,656,255 to Jones; and 6,596,740 to Jones; which are incorporatedherein by reference. Various exemplary ways to administer nicotine inthe form of an oral spray, such as for buccal administration, are setforth in U.S. Pat. Nos. 6,024,097 to Von Wielligh; US Pat. Pub. Nos.2003/0159702 to Lindell et al.; 2007/0163610 to Lindell et al. and2009/0023819 to Axelsson; EP 1458388 to Lindell et al.; and PCT WO2008/037470 to Axelsson et al., which are incorporated herein byreference. Nicotine-containing sprays have been marketed under thetradenames “Nicotrol NS,” “Quit” and “Zonnic.”

Various other ways to administer nicotine for the purpose of providing atherapeutic effect have been proposed. For example, it has beensuggested that nicotine can be incorporated into orally dissolving films(e.g., U.S. Pat. Nos. 6,709,671 to Zerbe et al.; 7,025,983 to Leung etal.; and 7,491,406 to Leung et al.; and US Pat. Pub. Nos. 2006/0198873to Chan et al. and 2006/0204559 to Bess et al.); oral osmotic devices(e.g., U.S. Pat. No. 5,147,654 to Place et al.); gum pads (e.g., U.S.Pat. No. 6,319,510 to Yates); oral patches (e.g., US Pat. Pub. No.2006/0240087 to Houze et al.); snuff-type forms in pouches or sachets(e.g., U.S. Pat. No. 4,907,605 to Ray et al. and US Pat. Pub. No.2009/0293895 to Axelsson et al.); lip balm (e.g., U.S. Pat. No.7,105,173 to Rolling) and beverages (e.g., U.S. Pat. Nos. 6,268,386 toThompson; 7,115,297 to Stillman; and 7,435,749 to Knight). It also hasbeen suggested that nicotine can be delivered using various types ofinhalation devices and vapor delivery systems (e.g., U.S. Pat. Nos.4,284,809 to Ray; 4,800,903 to Ray et al.; 6,234,169 to Bulbrook et al.;6,874,507 to Farr; and US Pat. Pub. Nos. 2006/0018840 toLechuga-Ballesteros and 2009/0005423 to Gonda; and EP 1,618,803 to Hon).

It would be desirable to provide a composition capable of delivering oradministering nicotine for therapeutic purposes.

BRIEF SUMMARY

In one aspect, the present invention relates to a composition intendedto be employed for therapeutic purposes. The composition includes a formthat is pharmaceutically effective or pharmaceutically acceptable. Thecomposition incorporates a nicotinic compound that is considered to benon-selective (i.e., is not considered to discriminate) among thevarious nAChRs in the CNS and PNS. An example of such a compound isnicotine. The composition incorporates at least one other nicotiniccompound. The other nicotinic compound is a compound that exhibitsselectivity to nicotinic receptor subtypes within the CNS. Othernicotinic compounds that are highly preferred act as agonists, andrepresentative agonists are selective to nAChRs such as α₇ and α₄β₂. Thenicotine can be as a free base (e.g., as a mixture of nicotine andmicrocrystalline cellulose), as another form of nicotine salt (e.g., asnicotine bitartrate) or as nicotine polacrilex. In a highly preferredembodiment, the composition that incorporates at least two nicotinicactive ingredients is provided in a single dosage form or unit, which isintended to be administered by oral means.

In another aspect, the present invention relates to a method forproviding treatment for a condition, disease or disorder. The methodinvolves administering to a human subject, such as a subject in needthereof, an effective amount of a composition incorporating a nicotiniccompound that is considered to be non-selective among the various nAChRsin the CNS and PNS (e.g., nicotine) and at least one other nicotiniccompound. The other nicotinic compound is a compound that exhibitsselectivity to nAChRs within the CNS. Other nicotinic compounds that arehighly preferred act as agonists, and are selective to nAChRs such as α₇and α₄β₂. In a highly preferred embodiment, the composition isadministered by oral means.

Compositions of the present invention, including compositionsincorporating other pharmaceutically acceptable excipient ingredients,can be provided in forms suitable for administration to human subjects.Exemplary formats and configurations for oral administration ofnicotine-containing compositions for therapeutic purposes include gum,tablet, lozenge, pouch and mouth-spray types of products.

Compositions of the present invention can be used to treat a widevariety of diseases, conditions and disorders, particularly those of theCNS. Additionally, those compositions can be used as smoking cessationaids (e.g., as components of NRT).

DETAILED DESCRIPTION OF THE DRAWINGS AND THE PRESENTLY PREFERREDEMBODIMENTS

The present inventions now will be described more fully hereinafter. Theinvention may be embodied in many different forms and should not beconstrued as limited to the embodiments set forth herein; rather, theseembodiments are provided so that this disclosure will satisfy applicablelegal requirements. As used in this specification and the claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise.

Embodiments of the present invention include the use of nicotiniccompounds for therapeutic purposes and provide compositions adapted fororal or nasal delivery of nicotinic compounds. As used herein,“nicotinic compound” refers to a compound capable of affecting anicotinic acetylcholinergic receptor (nAChR). Preferably, a nicotiniccompound is an agonist of a nicotinic acetylcholinergic receptor. Asused herein, “agonist” refers to a compound that binds to a receptor andtriggers a response. The term “agonist” includes full agonists, partialagonists and superagonists. Full agonists bind to the receptor and mimicthe response produced by binding of the natural ligand for the receptor.Partial agonists bind the receptor and produce a response, but are lessefficacious in producing the response as compared to the natural ligandfor the receptor. Superagonists bind the receptor and produce aresponse, but are more efficacious in producing the response as comparedto the natural ligand for the receptor. As used herein, a “source ofnicotine” refers to naturally-occurring or synthetic nicotine unboundfrom a plant material, meaning the compound is at least partiallypurified and not contained within a plant structure such as a tobaccoleaf. Most preferably, nicotine is naturally-occurring and obtained asan extract from a Nicotiana species (e.g., tobacco). The nicotine mayinclude the enantiomeric form S(−)-nicotine, R(+)-nicotine, or a mixtureof S(−)-nicotine and R(+)-nicotine. Most preferably, the nicotine is inthe form of S(−)-nicotine (e.g., in a form that is virtually allS(−)-nicotine) or an enantiomerically enriched mixture composedprimarily or predominantly of S(−)-nicotine (e.g., a mixture composed ofabout 95 weight parts S(−)-nicotine and about 5 weight partsR(+)-nicotine). Most preferably, the nicotine is employed in virtuallypure form or in an essentially pure form. Highly preferred nicotine thatis employed has a purity of greater than about 95 percent, morepreferably greater than about 98 percent, and most preferably greaterthan about 99 percent, on a weight basis. Despite the fact that nicotinecan be extracted from Nicotiana species, it is highly preferred that thenicotine (and the composition and products produced in accordance withthe present invention) are virtually or essentially absent of othercomponents obtained from or derived from tobacco.

The source of nicotine of the nicotine-containing compositions of theinvention can include nicotine in free base form, salt form, as acomplex, as a solvate, or other suitable form. See, for example, thediscussion of nicotine in free base form in US Pat. Pub. No.2004/0191322 to Hansson, which is incorporated herein by reference. Atleast a portion of the nicotinic compound can be employed in the form ofa resin complex of nicotine where nicotine is bound in an ion exchangeresin such as nicotine polacrilex. See, for example, U.S. Pat. No.3,901,248 to Lichtneckert et al.; which is incorporated herein byreference. At least a portion of the nicotine can be employed in theform of a salt. Salts of nicotine can be provided using the types ofingredients and techniques set forth in U.S. Pat. No. 2,033,909 to Coxet al. and Perfetti, Beitrage Tabakforschung Int., 12: 43-54 (1983),which are incorporated herein by reference. Additionally, salts ofnicotine have been available from sources such as Pfaltz and Bauer, Inc.and K&K Laboratories, Division of ICN Biochemicals, Inc. Furthermore,combinations of forms of nicotine, or combinations of nicotine salts,can be employed. See, for example, U.S. patent application Ser. No.12/769,335, filed Apr. 28, 2010, to Brinkley et al.; which isincorporated herein by reference.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein.

When nicotinic compounds of the present invention contain relativelybasic functionalities, as in nicotine, for example, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Exemplary pharmaceutically acceptable nicotine saltsinclude tartrate (e.g., nicotine tartrate and nicotine bitartrate),chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride),sulfate, perchlorate, ascorbate, fumarate, citrate, malate, lactate,aspartate, salicylate, tosylate, succinate, pyruvate, and the like;nicotine salt hydrates (e.g., nicotine zinc chloride monohydrate), andthe like. One skilled in the art will appreciate that analogous saltscan be formed for agonist compounds comprising relatively basicfunctionalities. Additional acids that can form salts include formic,acetic, propionic, isobutyric, butyric, alpha-methylbutyric, isovaleric,levulinic, beta-methylvaleric, caproic, 2-furoic, benzoic, phenylacetic,heptanoic, octanoic, nonanoic, oxalic, malonic, glycolic acid,benzenesulfonic, camphosulfonic, ethanesulfonic, gluconic, glucoronic,glutamic, hippuric, hydrobromic, isethionic, lactobionic, maleic,mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic,nitric, pamoic, pantothenic, phosphoric, sulfuric and the like as wellas other fatty acids having carbon chains of up to about 20 carbonatoms.

Although nicotinic compounds of the present invention may includerelatively acidic functionalities less frequently, base addition saltsmay be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Salts derived from pharmaceutically-acceptable inorganicbases include aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, manganous, potassium, sodium, zinc and thelike. Salts may also be derived from pharmaceutically-acceptable organicbases including salts of primary, secondary, tertiary and quaternaryamines.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain compounds may containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

In addition to salt forms, also included are compounds which are in apro-drug form. Pro-drugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds of the present invention.Additionally, pro-drugs can be converted to the compounds of the presentinvention by chemical or biochemical methods in an ex vivo environment.For example, pro-drugs can be slowly converted to the compounds of thepresent invention when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, bothsolvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present invention and may be used withinthe scope of the present invention.

The composition preferably includes another nicotinic compound otherthan nicotine, and most preferably, that nicotinic compound can becharacterized as a selective agonist to nicotinic receptor subtypes thatare present in the brain, or that can otherwise be characterized as acompound that modulates nicotinic receptor subtypes of the CNS. Variousnicotinic receptor subtypes are described in Dwoskin et al., Exp. Opin.Ther. Patents, 10: 1561-1581 (2000); Huang et al., J. Am. Chem. Soc.,127: 14401-14414 (2006) and Millar, Biochem. Pharmacol., 78: 766-776(2009); which are incorporated herein by reference. Representativecompounds that can be characterized as other nicotinic compounds forpurposes of this invention are set forth in Schmitt et al., AnnualReports in Med. Chem. 35: 41-51 (2000) and Arneric et al., Biochem.Pharmacol., 74: 1092-1101 (2007); which are incorporated herein byreference.

In one aspect, the other nicotinic compound can be a compound hasselectivity to the α₇ (alpha 7) nicotinic receptor subtype, andpreferably is an agonist of the α₇ nicotinic receptor subtype. Severalcompounds having such α₇ receptor subtype selectivity have been reportedin the literature. For example, various compounds purported to haveselectivity to the α₇ nicotinic receptor subtype are set forth in Malyszet al., Assay Drug Dev. Tech., August: 374-390 (2009). An example of onesuch nicotinic compound isN-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide(also known as TC-5619). See, for example, Hauser et al., Biochem.Pharmacol., 78: 803-812 (2009). Another representative is compound is(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine(also known as dianicline or SSR591813 or SSR-591,813). See, forexample, Hajos et al., J. Pharmacol. Exp. Ther., 312: 1213-1222 (2005).Another representative compound is1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester(also known as SSR180711). See, for example, Biton et al.,Neuropsychopharmacol., 32: 1-16 (2007). Another representative compoundis3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine(also known as GTS-21). See, for example, U.S. Pat. Nos. 5,516,802 toZoltewicz et al. and 5,741,802 to Kem et al. Another representativecompound is2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole(also known as A-582941). See, for example, Thomsen et al.,Neuroscience, 154: 741-753 (2008). Another representative compound is(5S)-spiro[1,3-oxazolidine-5,8′-1-azabicyclo[2.2.2]octane]-2-one (alsoknown as AR-R-17779 or AR-R-17779). See, for example, Li et al.,Neuropsycopharmacol., 33: 2820-2830 (2008). Another representativecompound is N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (alsoknown as PNU-282,987). See, for example, Siok et al., Eur. J. Neurosci.,23: 570-574 (2006). Another representative compound is5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide (alsoknown as WAY-317,538 or SEN-12333). See, for example, Roncarati et al.,J. Pharmacol. Exp. Ther., 329: 459-468 (2009). Yet other examples arecompounds are those designated as EVP-6124 and EVP-4473 by EnvivoPharmaceuticals, Inc., TC-6987 by Targacept, Inc. and MEM3454 by MemoryPharmaceuticals Corp. The foregoing cited references are incorporatedherein by reference.

In one aspect, the nicotinic compound other than nicotine can be acompound that has selectivity to the α₄β₂ (alpha 4 beta 2) nicotinicreceptor subtype, and preferably is an agonist of the α₄β₂ nicotinicreceptor subtype. Several compounds having such α₄β₂ receptor subtypeselectivity have been reported in the literature. An example of one suchnicotinic compound is known as7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine (alsoknown as varenicline and in the form of varenicline tartrate which isthe active ingredient of a product commercially marketed under thetradename Chantix or Champix by Pfizer). See, for example, Jorenby etal., JAMA, 296: 56-63 (2006) and US Pat. Pub. No. 2010/0004451 to Ahmedet al. Another representative compound is(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine (alsoknown as ispronicline or AZD-3480 of AstraZeneca or TC-1734 ofTargacept, Inc. (Winston-Salem N.C., USA)). See, for example, Dunbar etal., Psychopharmacol. (Berlin), 191: 919-929 (2007). Anotherrepresentative compound is[3-(2(S))-azetidinylmethoxy)pyridine]dihydrochloride, (also known asA-85380). See, for example, Schreiber, Psychopharmacol., 159:248-257(2002). Another representative compound is(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine(also known as SSR591813). See, for example, Cohen et al., Neuroscience,Pres. No. 811.5 (2002) and Cohen et al., J. Pharmacol. Exp. Ther., 306:407-420 (2003). Another representative compound is known as A-969933.See, for example, Zhu et al., Biochem. Pharmacol., 78: 920 (2009). Otherrepresentative compounds are known as S35836-1 and S35678-1. See, forexample, Lockhart et al., Neuroscience, Pres. No. 684.9 (2002). Yetother examples are compounds are those designated as3-(5,6-Dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptane (alsoknown as Sofinicline or ABT-894) by Abbott Laboratories; AZD1446 byAstraZeneca and TC-6499 by Targacept, Inc. The foregoing citedreferences are incorporated herein by reference.

The compositions of the invention preferably include a form that ispharmaceutically effective and pharmaceutically acceptable. That is, thecomposition most preferably does not incorporate to any appreciabledegree, or does not purposefully incorporate, components of tobacco,other than nicotine. As such, pharmaceutically effective andpharmaceutically acceptable compositions do not include tobacco,processed tobacco components, or many of the components of tobaccotraditionally present within tobacco-containing cigarettes, cigars,pipes, or smokeless forms of tobacco products. Highly preferredcompositions that are derived by extracting naturally-occurring nicotinefrom tobacco include less than 0.5 weight percent of tobacco componentsother than nicotine, more often less than about 0.25 weight percent, andtypically are entirely absent or devoid of components of tobacco,processed tobacco components, or components derived from tobacco, otherthan nicotine, based on the total weight of the composition.

The pharmaceutical compositions of the invention may be convenientlymade available in a unit dosage form, whereby such formulations may beprepared by any of the methods generally known in the pharmaceuticalarts. Such methods of preparation comprise combining (by variousmethods) an active agent with a suitable carrier or other adjuvant,which may consist of one or more ingredients. The combination of theactive ingredient with the one or more adjuvants is then physicallytreated to present the formulation in a suitable form for delivery(e.g., shaping into a tablet or forming an aqueous suspension).

The nicotine-containing pharmaceutical compositions of the invention canincorporate various pharmaceutically acceptable excipients. By“pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended a carrier or excipient that is conventionallyused in the art to facilitate the storage, administration, and/or thehealing effect of an active agent (e.g., a nicotinic compound). Thecarrier(s) are preferably pharmaceutically acceptable in the sense ofbeing compatible with the other ingredients of the formulation and notunduly deleterious to the recipient thereof. A carrier may also reduceany undesirable side effects of the agent. See, Wang et al., J. Parent.Drug Assn., 34(6): 452-462 (1980), which is incorporated herein byreference. Exemplary pharmaceutical excipients and/or additives suitablefor use in the compositions according to the invention are listed inRemington: The Science & Practice of Pharmacy, 21^(st) ed., LippincottWilliams & Wilkins (2006); in the Physician's Desk Reference, 64^(th)ed., Thomson PDR (2010); and in Handbook of Pharmaceutical Excipients,6^(th) ed., Eds. Raymond C. Rowe et al., Pharmaceutical Press (2009),which are incorporated herein by reference.

The identity and quantity used of different excipients can vary, and theselection and amount of each excipient can depend upon factors such asthe ultimate form and function of product that is desired. See, forexample, the types of ingredients, relative amounts and combinations ofingredients, nicotine-containing formulations and preparation processesfor nicotine-containing products set forth in U.S. Pat. Nos. 5,512,306to Carlsson et al.; 5,525,351 to Dam; 5,549,906 to Santus; 5,711,961 toReiner et al.; 5,811,126 to Krishnamurthy; 5,939,100 to Albrechtsen etal.; 6,024,981 to Khankari et al.; 6,083,531 to Humbert-Droz et al.;6,090,401 to Gowan, Jr. et al.; 6,110,495 to Dam; 6,248,760 toWilhelmsen; 6,280,761 to Santus; 6,426,090 to Ream et al.; 6,569,463 toPatel et al.; 6,583,160 to Smith et al.; 6,585,997 to Moro et al.;6,676,959 to Andersson et al.; 6,893,654 to Pinney et al.; 7,025,983 toLeung et al. and 7,163,705 Johnson et al.; US Pat. Pub. Nos.2003/0176467 to Andersson et al.; 2003/0235617 to Martino et al.;2004/0096501 to Vaya et al.; 2004/0101543 to Liu et al.; 2004/0191322 toHansson; 2005/0053665 to Ek et al.; 2005/0123502 to Chan et al.;2008/0038209 to Andersen et al.; 2008/0286341 to Andersson et al.;2009/0023819 to Axelsson; 2009/0092573 to Andersen; 2010/0004294 toAxelsson et al. and 2010/0061940 to Axelsson et al., which areincorporated herein by reference.

Representative types of excipients that are particularly useful for themanufacture of nicotine-containing products include fillers or carriersfor active ingredients (e.g., calcium polycarbophil, microcrystallinecellulose, cornstarch, silicon dioxide or calcium carbonate),thickeners, film formers and binders (e.g., hydroxypropyl cellulose,hydroxypropyl methylcellulose, acacia, sodium alginate, xanthan gum andgelatin), buffers and pH control agents (e.g., magnesium oxide,magnesium hydroxide, potassium carbonate, sodium carbonate, potassiumbicarbonate, sodium bicarbonate, or mixtures thereof), antiadherents(e.g., talc), glidants (e.g., colloidal silica), natural or artificialsweeteners (e.g., saccharin, acesulfame K, aspartame, sucralose,isomalt, lactose, mannitol, sorbitol, xylitol and sucrose), humectants(e.g., glycerin), preservatives and antioxidants (e.g., sodium benzoateand ascorbyl palmitate), surfactants (e.g., polysorbate 80), natural orartificial flavors (e.g., mint, cinnamon, cherry or other fruitflavors), dyes or pigments (e.g., titanium dioxide or D&C Yellow No.10), and lubricants or processing aids (e.g, calcium stearate ormagnesium stearate). Certain types of nicotine-containing products alsocan have outer coatings composed of ingredients capable of providingacceptable outer coatings (e.g., an outer coating can be composed ofingredients such as carnauba wax, and pharmaceutically acceptable formsof shellacs, glazing compositions and surface polish agents).

Representative compositions incorporating a source of nicotine andanother nicotinic compound as active ingredients can have various typesof formats and configurations, and as a result, the character, nature,behavior, consistency, shape, form, size and weight of the compositioncan vary. The shape of a representative composition can be generallyspherical, cylindrical (e.g., ranging from the general shape of aflattened disc to the general shape of a relatively long, slenderstick), helical, obloid, square, rectangular, or the like; or thecomposition can have the form of a bead, granular powder, crystallinepowder, capsule, film, strip, gel, or the like. The shape of thecomposition can resemble a wide variety of pill, tablet, lozenge, minilozenge, capsule, caplet, pouch and gum types of products thattraditionally have been employed for the administration ofpharmaceutical types of products. The general nature of a representativecomposition can be soft or hard to the touch or of intermediate softnessor hardness; and as such, the composition can be considered to bemalleable, flexible, chewy, resilient, brittle, or the like. Whenadministered orally, various components of the product can be consideredto be readily dispersible or slow to disperse, or those variouscomponents can dissolve at varying rates (e.g., from relatively fast torelatively slow). As a result, for compositions ingested by insertion inthe mouth of the human subject, the release rate of active ingredientduring use of the product can vary from relatively fast to relativelyslow, depending upon factors such as the design of the product and theuse of product by the subject using that product. See also, by way ofexample, the types of products proposed in U.S. Pat. Nos. 4,655,231 toRay et al.; 5,147,654 to Place et al.; 5,543,424 to Carlsson et al.;6,268,386 to Thompson; 6,319,510 to Yates; 6,488,953 Halliday et al.;6,709,671 to Zerbe et al.; 7,025,983 to Leung et al.; 7,105,173 toRolling; 7,115,297 to Stillman; 7,435,749 to Knight and 7,491,406 toLeung et al.; and US Pat. Pub. Nos. 2004/0191322 to Hansson;2006/0198873 to Chan et al.; 2006/0240087 to Houze et al.; 2006/0204559to Bess et al.; 2007/0269492 to Steen et al.; 2008/0020050 to Chau etal.; 2008/0286340 to Andersson et al.; 2008/0292683 to Sanghvi et al.and 2009/0004248 to Bunick et al., which are incorporated herein byreference.

Compositions of the present invention may include short-term,rapid-onset, rapid-offset, controlled release, sustained release,delayed release, and pulsatile release formulations, providing theformulations achieve administration of a nicotinic compound as describedherein. See Remington's Pharmaceutical Sciences, 18^(th) ed.; MackPublishing Company, Eaton, Pa., (1990), which is incorporated herein byreference.

Solid dosage forms may be formulated so as to provide a delayed releaseof the active agent (i.e., the nicotinic compounds), such as byapplication of a coating. Delayed release coatings are known in the art,and dosage forms containing such may be prepared by any known suitablemethod. Such methods generally involve application of a delayed releasecoating composition after preparation of the solid dosage form (e.g., atablet or caplet). Application of the coating may be be implementedusing methods such as airless spraying, fluidized bed coating, use of acoating pan, or the like. Materials for use as a delayed release coatingcan be polymeric in nature, such as cellulosic material (e.g., cellulosebutyrate phthalate, hydroxypropyl methylcellulose phthalate, andcarboxymethyl ethylcellulose), and polymers and copolymers of acrylicacid, methacrylic acid, and esters thereof.

Solid dosage forms according to the present invention may also providesustained release (i.e., releasing the active agent over a prolongedperiod of time), and may or may not also provide delayed release.Sustained release formulations are known in the art and are generallyprepared by dispersing the active ingredient within a matrix of agradually degradable or hydrolyzable material, such as an insolubleplastic, a hydrophilic polymer, or a fatty compound. Alternatively, asolid dosage form may be coated with such a material.

The manners and methods used to formulate and manufacture thecomposition can vary. Typical conditions associated with manufacture ofpharmaceutical types of products include control of heat and temperature(i.e., the degree of heat to which the various ingredients are exposedduring manufacture and the temperature of the manufacturingenvironment), moisture content (e.g., the degree of moisture presentwithin individual ingredients and within the final composition),humidity within the manufacturing environment, airflow experienced bythe various ingredient during the manufacturing process, and othersimilar types of factors. Additionally, various process steps involvedin product manufacture can involve selection of certain solvents andprocessing aids, use of heat and radiation, refrigeration and cryogenicconditions, and the like. The manufacturing conditions also can becontrolled due to selection of the form of various ingredients (e.g.,solid, liquid or gas), particle size or crystalline nature ofingredients of solid form, concentration of ingredients in liquid form,or the like. Ingredients can be processed into the desired compositionby techniques such as extrusion, compression, spraying, and the like.

The manners and methods for incorporating the nicotinic compounds (i.e.,the source of nicotine and the other nicotinic compound) into thenicotine-containing composition can vary. The location of each of theactive ingredients within the composition can vary. The nicotiniccompounds can be located throughout the composition or in selectedregions of the composition (e.g., homogeneously throughout thecomposition, in an outer coating of the composition or in the region ofthe composition occupied by nicotine or in selected layer(s) of alaminated composition). As such, certain regions of the composition canbe essentially devoid of any or all nicotinic compounds, there can exista concentration gradient of various nicotinic compounds within orthroughout the composition, or a certain region of the composition canhave a relatively high concentration of some or all of the nicotiniccompounds relative to other regions of that composition. Compositionscan be co-extruded, laminated or formed so as to have sandwich-typeforms; and hence the location of nicotine, other nicotinic compound andother ingredients can be controlled in order to provide the desiredfeatures such as performance, behavior, interaction or non-interactionwith other ingredients, storage stability, and the like. In addition,mixtures of component ingredients can be formulated and manufacturedinto core/shell types of configurations (e.g., gum or lozenge types ofproducts that have an inner region and at least one additionaloverlayer), with the various regions of such products having differingoverall compositions or properties. Thus, for example, any or all of theother nicotinic compounds can have relatively high concentrationstowards the inner region of the product, or relatively highconcentrations towards the outer region of the product.

The other nicotinic compound can be mixed with the source of nicotine(e.g., with nicotine salts), and incorporated into the composition as amixture. Various forms of nicotine and the other nicotinic compound alsocan be introduced into the composition at different times or stages ofthe manufacturing process, or in combination with different ingredientsemployed in the manufacturing process. Alternatively, the other nicotinecompound can be segregated from the nicotine within the composition(e.g., by physically locating the other nicotinic compound and nicotineat separate locations within the composition, or by segregating thenicotinic compound and nicotine using encapsulation or other types ofchemical means to separate those components).

In one embodiment, at least one of nicotine and the nicotinic compoundcan be sorbed onto a porous particulate carrier material, such asmicrocrystalline cellulose (MCC). In one embodiment, the MCC materialsso employed have an average particle size range of about 15 to about 250microns. Exemplary MCC materials include various grades of AVICEL® andVIVACEL® materials. See, for example, US Pat. Pub. No. 2004/0191322 toHansson, which is incorporated herein by reference. Thus, in certainembodiments, multiple forms of nicotinic compounds can be sorbed ontothe particulate carrier including any of the various nicotinic compoundcombinations discussed herein, such as nicotine free base combined witha nicotinic compound salt, two nicotinic salts (e.g., a nicotinelevulinate/nicotine tartrate mixture or a nicotine levulinate/nicotinebitartrate mixture), and the like. The nicotine compound can be sorbedonto the particulate carrier by, for example, dissolving the nicotiniccompound in a hydrophilic solvent (e.g., water, alcohol, or mixturesthereof) and combining the solution with the particulate carrier,followed by drying to remove the solvent. The particulate carriermaterial with sorbed nicotinic compound can be combined with othercarriers or excipients in order to provide a composition adapted fororal or nasal delivery of the active ingredients.

In use, the compositions of the present invention most preferably areadministered by oral ingestion. For example, nicotine-containingcompositions can be administered and employed using the manners andmethods typically used for the administration of traditional types ofnicotine containing gums, lozenges, pouch product and sprays.

One particularly preferred type of a representative compositionincorporating a source of nicotine and another nicotinic compound asactive ingredients, and that provides nicotine delivery in anon-inhalable form, has the form of a gum or other type of similarlychewable product. Gum forms of product include gum base (e.g., typicallythe types of pharmaceutically acceptable gum bases available fromsources such as Gum Base Co. S.p.a., Wm. J. Wrigley Jr. Company orGumlink A/S). See, for example, the types of nicotine-containing gums,gum formulations, gum formats and configurations, gum characteristicsand techniques for formulating or manufacturing gums are set forth inU.S. Pat. Nos. 3,845,217 to Ferno et al.; 3,877,468 to Lichtneckert etal.; 3,901,248 to Lichtneckert et al.; 5,154,927 to Song et al.;6,322,806 to Ream et al.; 6,344,222 to Cherukuri et al.; 6,355,265 toReam et al.; 6,358,060 to Pinney et al.; 6,773,716 to Ream et al.;6,893,654 to Pinney et al.; 7,101,579 Athanikar et al.; 7,163,705 toJohnson et al. and 7,208,186 to Norman et al.; US Pat. Pub. Nos.2004/0194793 to Lindell et al.; 2006/0099300 to Andersen et al.;2006/0121156 to Andersen et al.; 2006/0165842 to Andersen et al.;2006/0204451 to Salini; 2006/0246174 to Andersen et al.; 2006/0275344 toMody et al.; 2007/0014887 to Cherukuri et al.; 2007/0269386 to Steen etal. and 2009/0092573 to Andersen and PCT WO 2007/104574 to Axelsson etal.; which are incorporated herein by reference. The amount ofcomposition contained within each piece of unit of gum type of productcan vary. For example, representative unit or gum types of productsgenerally weigh at least about 0.5 g, often at least about 1 g, andfrequently at least about 1.5 g, of composition; while the weight ofsuch types of products generally does not exceed about 3 g, often doesnot exceed about 2.5 g, and frequently does not exceed about 2 g. Thetime period over which the gum piece can be chewed can vary; andtypically, each piece of gum is chewed for at least about 5 minutes,often at least about 10 minutes, while each piece of gum typically ischewed for up to about 40 minutes, often up to about 30 minutes.

Another particularly preferred type of a representative compositionincorporating a source of nicotine and another nicotinic compound asactive ingredients, and that provides nicotine delivery in anon-inhalable form, has the form of a lozenge, tablet, microtab, orother type tablet-type product. See, for example, the types ofnicotine-containing lozenges, lozenge formulations, lozenge formats andconfigurations, lozenge characteristics and techniques for formulatingor manufacturing lozenges set forth in U.S. Pat. Nos. 4,967,773 to Shaw;5,110,605 to Acharya; 5,733,574 to Dam; 6,280,761 to Santus; 6,676,959to Andersson et al.; 6,248,760 to Wilhelmsen and 7,374,779; US Pat. Pub.Nos. 2001/0016593 to Wilhelmsen; 2004/0101543 to Liu et al.;2006/0120974 to Mcneight; 2008/0020050 to Chau et al. and 2009/0081291to Gin et al.; PCT WO 91/09599 to Carlsson et al. and PCT WO 2007/104575to Axelsson; which are incorporated herein by reference. The amount ofcomposition contained within each piece or unit of lozenge type ofproduct can vary. For example, representative units of lozenge types ofproducts generally weigh at least about 100 mg, often at least about 200mg, and frequently at least about 300 mg, of composition; while theweight of such types of products generally does not exceed about 1.5 g,often does not exceed about 1 g, and frequently does not exceed about0.75 g.

Another particularly preferred type of a representative compositionincorporating a source of nicotine and another nicotinic compound asactive ingredients, and that provides nicotine delivery in anon-inhalable form, has the form of a pouch or sachet type of product.See, for example, the types of pouch materials and nicotine-containingformulations set forth in PCT WO 2007/104575 to Axelsson et al.; whichis incorporated herein by reference. See also, for example, the types ofpouch materials and pouch manufacturing techniques(e.g., filling andsealing techniques) set forth in US Pat. Pub. No. 2010/0018539 toBrinkley et al.; which is incorporated herein by reference. The amountof composition contained within each pouch can vary. For example,representative pouch products generally contain at least about 75 mg,often at least about 100 mg, and frequently at least about 150 mg, ofcomposition; while the amount of composition contained in representativepouch products generally does not exceed about 500 mg, often does notexceed about 400 mg, and frequently does not exceed about 300 mg.

The amount of nicotine active ingredient within the overall compositioncan vary. For a composition intended for oral consumption by insertioninto the mouth of the subject (e.g., chewable piece of gum product, alozenge, a pouch product, or the like), the amount of nicotine withineach dosage piece or unit typically is at least about 0.5 mg, generallyis at least 1 mg, often is at least about 1.5 mg and frequently is atleast about 2 mg; while the amount of nicotine within each piecetypically does not exceed about 10 mg, generally does not exceed about 8mg, often does not exceed about 6 mg and frequently does not exceedabout 5 mg. Exemplary types of such products incorporate about 2 mg,about 2.5 mg, about 3.5 mg and about 4 mg of nicotine per piece or unit(calculated as nicotine free base).

The amount of the other nicotinic compound active ingredient within theoverall composition can vary. For a composition intended for oralconsumption by insertion into the mouth of the subject (e.g., chewablepiece of gum product, a lozenge, a pouch product, or the like), theamount of other nicotinic compound within each dosage piece or unittypically does not exceed about 100 mg, generally does not exceed about75 mg, often does not exceed about 50 mg. The amount of other nicotiniccompound within each dosage piece or unit generally is at least about0.1 mg, typically is at least about 0.5 mg and often is at least 1 mg.Depending upon the pharmacological effect provided by the othernicotinic compound, the amount of that compound within each dosage pieceor unit typically can be at least about 2 mg and often can be at leastabout 5 mg. Exemplary types of such products incorporate about 0.5 mg,about 1 mg, about 25 mg and about 50 mg of other nicotinic compound perpiece or unit.

Another particularly preferred type of a representative compositionincorporating a source of nicotine and another nicotinic compound activeingredient has the form of a spray. See, for example, the types of spraymaterials and nicotine-containing spray formulations set forth in U.S.Pat. Nos. 4,579,858 to Ferno et al.; 5,656,255 to Jones; 6,024,097 toVon Wielligh and 6,596,740 to Jones; US Pat. Pub. Nos. 2003/0159702 toLindell et al. and 2007/0163610 to Lindell et al.; EP 1458388 to Lindellet al.; PCT WO 2006/100075 to Axelsson and PCT WO 2008/037470 toAxelsson et al.; which are incorporated herein by reference. Preferredspray form products produce sprays or mists using nebulizers or othertypes of devices for producing aerosols by mechanical means. Preferredspray types of products employ liquid solvents or carriers (e.g., wateror water/ethanol mixtures) that contain nicotine and the other nicotiniccompound. The concentration of the nicotine within the liquid sprayformulation can vary, but typically is in the range of about 0.5 percentto about 5 percent, often about 1percent to about 3 percent, based onthe total weight of the liquid formulation. Depending upon the identityof the other nicotinic compound incorporated within the sprayformulation, the concentration of the other nicotinic compound withinthe liquid spray formulation typically is in the range of about 0.1percent to about 15 percent, often about 0.2 percent to about 10percent, based on the total weight of the liquid formulation.

Although the compositions of the invention are preferably non-inhalable,it is possible to formulate the above-noted combinations of nicotiniccompounds in a form capable of pulmonary delivery using various types ofinhalation devices and vapor delivery systems designed to deliver anactive agent to the lungs as opposed to buccal, sublingual, or nasaldelivery. See, for example, the types of inhalable formulations andvapor delivery devices and systems set forth in U.S. Pat. Nos. 4,284,809to Ray; 4,800,903 to Ray et al.; 5,167,242 to Turner et al.; 6,098,632to Turner et al.; 6,234,169 to Bulbrook et al. and 6,874,507 to Farr; USPat. Pub. Nos. 2004/0034068 to Warchol et al; 2006/0018840 toLechuga-Ballesteros; 2008/0302375 to Andersson et al. and 2009/0005423to Gonda; and EP 1,618,803 to Hon, which are incorporated herein byreference.

Though not preferred, compositions of the present invention can beadministered in a transdermal manner. See, for example, the types oftransdermal delivery technologies set forth in U.S. Pat. Nos. 4,597,961to Etscom; 5,298,257 to Bannon et al.; 5,603,947 to Wong et al.;5,834,011 to Rose et al.; 6,165,497 to Osborne et al. and 6,676,959 toAnderson et al and PCT WO 2007/012963 to Johnson et al.; which areincorporated herein by reference.

For compositions of the present invention, the intended dose of thenicotine active ingredient can vary. The overall dose of that activeingredient can depend upon factors such as the weight of the subjectingesting the composition, the condition, disease or disorder beingtreated, the state or severity of the condition, disease or disorderbeing treated, the desired pharmacological effect, or other suchfactors. Typically, the amount of nicotine active ingredientadministered to a subject per day is at least about 2 mg, often is atleast about 4 mg, and frequently is at least about 10 mg. Typically, theamount of nicotine active ingredient administered to a subject per daydoes not exceed about 60 mg, often does not exceed about 50 mg, andfrequently does not exceed about 40 mg. The dose of nicotine, whether ona per dose or on an overall daily basis, is such that the subject doesnot experience untoward side effects resulting from overexposure of thatsubject to nicotine. See also, for example, the types of dosing regimensand administration techniques set forth in U.S. Pat. Nos. 6,660,754 toKyle et al. and US Pat. Pub. Nos. 2004/0006113 to Sachs; 2005/0214229 toPinney et al. and 2008/0124283 to Andersen and PCT WO 2007/104573 toAxelsson et al.; which are incorporated herein by reference.

For compositions of the present invention, the intended dose of theother nicotinic compound active ingredient can vary. The overall dose ofthat active ingredient can depend upon factors such as the weight of thesubject ingesting the composition, the condition being treated, thestate or severity of the disease or disorder being treated, the desiredpharmacological effect, the potency of that active ingredient, theamount of nicotine present in the composition in combination with thatactive ingredient, or other such factors. Typically, the amount of othernicotinic compound active ingredient administered to a subject per daydoes not exceed about 75 mg, and often does not exceed about 50 mg. Forcertain other nicotinic compound active ingredients, the amountadministered to a subject per day typically does not exceed 10 mg, andoften does not exceed about 5 mg. A highly preferred dose of the othernicotinic compound is such that sufficient compound is administered toprovide the desired CNS effect (e.g., due to the effect of that compoundat nAChRs within the CNS), while not sufficiently high so as to causeprovide side effects associated with toxicity or unwanted side effectsresulting from significant interaction of that compound at nAChRs withinthe PNS.

For compositions of the present invention, the amount nicotine activeingredient relative the amount of other nicotinic compound activeingredient in each dosage source or unit can vary. In one regard, theamount of nicotine active ingredient can be less than, approximatelyequal to or exceed the amount of the other nicotinic compound activeingredient, on a weight basis. For example, a piece gum or lozenge canincorporate about 1 to about 5 mg of nicotine, and about 0.1 mg to about2 mg of either a compound known as varenicline or an agonist of an α₇nicotinic receptor subtype or an α₄β₂ nicotinic receptor subtype. In oneregard, the amount of the other nicotinic compound active ingredient canexceed the amount of the nicotine active ingredient, on a weight basis.For example, a piece gum or lozenge can incorporate about 1 to about 5mg of nicotine, and about 10 mg to about 75 mg of either a compoundknown as AZD-3480 or a compound known as TC-5619.

The dose of the combination of active ingredients is that amounteffective to treat some symptoms of, or prevent occurrence of thesymptoms of, the condition, disease or disorder from which the subjector patient suffers. By “effective amount,” “therapeutic amount” or“effective dose” is meant that amount sufficient to elicit the desiredpharmacological or therapeutic effects, thus resulting in effectiveprevention or treatment of the condition, disease or disorder. Thus, aneffective amount of active ingredients is an amount sufficient to enterrelevant regions of the body (e.g., to pass across the blood-brainbarrier of the subject), to bind to relevant receptor sites in the CNSand PNS of the subject, and to elicit neuropharmacological effects(e.g., elicit neurotransmitter secretion, thus resulting in effectiveprevention or treatment of the condition, disease or disorder).Prevention of the disorder is manifested by delaying the onset of thesymptoms of the condition, disease or disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thecondition, disease or disorder or an amelioration of the reoccurrence ofthe symptoms thereof.

In use, the sources of nicotine and the other nicotinic compound activeingredients are administered in combination with one another. Forexample, pharmaceutically effective amounts of each active ingredientpreferably are incorporated into a single dosage source or unit (e.g.,an individual piece of gum, a single lozenge, or the like, andpreferably by ingestion by oral means). The nicotine active ingredientis an example of an ingredient that, at the dose administered, binds toand activates various nicotinic receptor subtypes located in both theCNS and the PNS. Hence, at the dose administered, the nicotine activeingredient does not discriminate (from the standpoint of its ability toundergo binding and elicit activation) among the various nAChRsexpressed in the CNS and PNS. As such, administration of nicotineintroduces CNS effects as well as PNS effects at peripheral sites (e.g.,neuromuscular, cardiovascular and gastrointestinal sites). Conversely,the other nicotinic compound active ingredient is selective to certainnAChRs expressed in the CNS. That is, the other nicotinic compoundactive ingredient, at the dose administered, exhibits an affinity tobind to and activate nicotinic receptor subtypes located in the CNS.Thus, administration of the combination of nicotinic compound activeingredients provides CNS effects (e.g., as a result of theadministration of the combination of nicotine and the other nicotiniccompound) and PNS effects (e.g., principally or virtually entirely as aresult of the administration of nicotine). As such, it is highlypreferred that the other nicotinic compound be administered within therelevant “therapeutic window” or within the “therapeutic index” of thatcompound, and that the dose of that other nicotinic compound be within adosage range sufficient that the compound elicits a desirable responsewithin the CNS while effects of that compound upon the PNS are avoidedto any significant extent. See, for example, Bencherif et al., J.Pharmacol. Exp. Ther., 279: 1413-1421 (1996) and U.S. Pat. No. 5,583,140to Bencherif et al.; which are incorporated herein by reference.

The compositions of the present invention can be used for treatment of awide variety of conditions, diseases and disorders. The compositions canbe used to treat those types of conditions, diseases and disorders thathave been reported to be treatable through the use or administration ofnicotine. As such, the compositions can be used to treat various CNSconditions, diseases and disorders, and the compositions also can beused as smoking cessation aids (i.e., as components of NRT).

The following examples are provided in order to further illustrate theinvention but should not be construed as limiting the scope thereof.Unless otherwise noted, all parts and percentages are by weight.

EXAMPLE 1

A lozenge generally similar in shape and form to a lozenge incorporating0.5 mg varenicline in the form of the tartrate salt of the activeingredient of a product commercially marketed under the tradenameChantix by Pfizer Incorporated is produced using generally similarexcipient ingredients and processing conditions used for the manufactureof the commercial lozenge, except that the varenicline active ingredientreplaced by a mixture of nicotine polacrilex and varenicline. The amountof nicotine polacrilex incorporated into each lozenge is such that theamount of nicotine active ingredient within each lozenge from thatsource is 2 mg; and the amount of varenicline incorporated into eachlozenge is such that the amount of that active ingredient within eachlozenge is 0.5 mg. As such, each lozenge (i.e., each dosing unit)incorporates both nicotine and a nicotinic compound purported to haveselectivity to the α₄β₂ nicotinic receptor subtype.

EXAMPLE 2

A lozenge generally similar in shape and form to a lozenge incorporating0.5 mg varenicline and commercially available as Chantix is producedusing generally similar excipient ingredients and processing conditionsused for the manufacture of the commercial lozenge, except that thevarenicline active ingredient replaced by a mixture of nicotinepolacrilex and varenicline. The amount of nicotine polacrilexincorporated into each dosage unit (i.e., each lozenge) is such that theamount of nicotine active ingredient within each lozenge from thatsource is 3 mg; and the amount of varenicline incorporated into eachlozenge is such that the amount of that active ingredient within eachlozenge is 0.1 mg. As such, each lozenge (i.e., each dosing unit)incorporates both nicotine and a nicotinic compound purported to haveselectivity to the α₄β₂ nicotinic receptor subtype.

EXAMPLE 3

A gum generally similar in shape and form to a nicotine-containing gumincorporating 4 mg of nicotine and commercially available as NicoretteOriginal Gum (distributed by GlaxoSmithKline Consumer Healthcare, L.P.)is produced using generally similar excipient ingredients and processingconditions used for the manufacture of the commercial gum, except thatthe nicotine polacrilex thereof is replaced by a mixture of nicotinepolacrilex and a compound known as varenicline (e.g., in the form of thetartrate salt found in Chantix). The amount of nicotine polacrilexincorporated into each chewing piece of gum is such that the amount ofnicotine active ingredient within each chewing piece from that source is3 mg; and the amount of varenicline active ingredient incorporated intoeach chewing piece of gum is such that the amount of active ingredientwithin each chewing piece from that source is 1 mg. As such, eachchewing piece of the gum product (i.e., each dosing unit) incorporatesboth nicotine and a nicotinic compound purported to have selectivity tothe α₄β₂ nicotinic receptor subtype.

EXAMPLE 4

A gum generally similar in shape and form to a nicotine-containing gumincorporating 4 mg of nicotine and commercially available as NicoretteOriginal Gum (distributed by GlaxoSmithKline Consumer Healthcare, L.P.)is produced using generally similar excipient ingredients and processingconditions used for the manufacture of the commercial gum, except thatthe nicotine polacrilex thereof is replaced by a mixture of nicotinepolacrilex and a compound known as varenicline (e.g., in the form of thetartrate salt found in Chantix). The amount of nicotine polacrilexincorporated into each dosage unit (i.e., into each chewing piece ofgum) is such that the amount of nicotine active ingredient within eachchewing piece from that source is 3 mg; and the amount of vareniclineactive ingredient incorporated into each chewing piece of gum is suchthat the amount of active ingredient within each chewing piece from thatsource is 0.2 mg. As such, each chewing piece of the gum product (i.e.,each dosing unit) incorporates both nicotine and a nicotinic compoundpurported to have selectivity to the α₄β₂ nicotinic receptor subtype.

EXAMPLE 5

A gum generally similar in shape and form to a nicotine-containing gumincorporating 4 mg of nicotine and commercially available as NicoretteOriginal Gum (distributed by GlaxoSmithKline Consumer Healthcare, L.P.)is produced using generally similar excipient ingredients and processingconditions used for the manufacture of the commercial gum, except thatthe nicotine polacrilex thereof is replaced by a mixture of nicotinepolacrilex and a compound of Targacept, Inc, (Winston-Salem, N.C., USA),known as TC-5619. In one aspect, the amount of nicotine polacrilexincorporated into each chewing piece of gum is such that the amount ofnicotine active ingredient within each chewing piece from that source is3 mg; and the amount of TC-5619 (active ingredient in free base form)incorporated into each chewing piece of gum is such that the amount ofactive ingredient within each chewing piece from that source is 1 mg. Ina second aspect, the amount of nicotine polacrilex incorporated intoeach chewing piece of gum is such that the amount of nicotine activeingredient within each chewing piece from that source is 3 mg; and theamount of TC-5619 (active ingredient in free base form) incorporatedinto each chewing piece of gum is such that the amount of activeingredient within each chewing piece from that source is 5 mg. In athird aspect, the amount of nicotine polacrilex incorporated into eachchewing piece of gum is such that the amount of nicotine activeingredient within each chewing piece from that source is 3 mg; and theamount of TC-5619 (active ingredient in free base form) incorporatedinto each chewing piece of gum is such that the amount of activeingredient within each chewing piece from that source is 25 mg. As such,each chewing piece of the gum product (i.e., each dosing unit)incorporates nicotine and a nicotinic compound purported to haveselectivity to the α₇ nicotinic receptor subtype.

EXAMPLE 6

A gum generally similar in shape and form to a nicotine-containing gumincorporating 4 mg of nicotine and commercially available as NicoretteOriginal Gum (distributed by GlaxoSmithKline Consumer Healthcare, L.P.)is produced using generally similar excipient ingredients and processingconditions used for the manufacture of the commercial gum, except thatthe nicotine polacrilex thereof is replaced by a mixture of nicotinepolacrilex and a compound of AstraZeneca known as AZD-3480((2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine). In oneaspect, the amount of nicotine polacrilex incorporated into each chewingpiece of gum is such that the amount of nicotine active ingredientwithin each chewing piece from that source is 3 mg; and the amount ofAZD-3480 incorporated into each chewing piece of gum is such that theamount of active ingredient within each chewing piece from that sourceis 25 mg. In another aspect, the amount of nicotine polacrilexincorporated into each chewing piece of gum is such that the amount ofnicotine active ingredient within each chewing piece from that source is3 mg; and the amount of AZD-3480 incorporated into each chewing piece ofgum is such that the amount of active ingredient within each chewingpiece from that source is 50 mg. As such, each chewing piece of the gumproduct (i.e., each dosing unit) incorporates nicotine and a nicotiniccompound purported to have selectivity to the α₄β₂ nicotinic receptorsubtype.

EXAMPLE 7

A coated gum generally similar in shape and form to anicotine-containing gum incorporating 4 mg of nicotine and commerciallyavailable as Nicorette Fruit Chill Gum (distributed by Walgreen Co.) isproduced using generally similar excipient ingredients and processingconditions used for the manufacture of the commercial gum, except thatthe nicotine polacrilex thereof is replaced by a mixture of nicotinepolacrilex and a compound of Targacept, Inc. known as TC-5619. In oneaspect, the amount of nicotine polacrilex incorporated into each chewingpiece of gum is such that the amount of nicotine active ingredientwithin each chewing piece from that source is 3 mg; and the amount ofTC-5619 (active ingredient in free base form) incorporated into eachchewing piece of gum is such that the amount of active ingredient withineach chewing piece from that source is 1 mg. In a second aspect, theamount of nicotine polacrilex incorporated into each chewing piece ofgum is such that the amount of nicotine active ingredient within eachchewing piece from that source is 3 mg; and the amount of TC-5619(active ingredient in free base form) incorporated into each chewingpiece of gum is such that the amount of active ingredient within eachchewing piece from that source is 5 mg. In a third aspect, the amount ofnicotine polacrilex incorporated into each chewing piece of gum is suchthat the amount of nicotine active ingredient within each chewing piecefrom that source is 3 mg; and the amount of TC-5619 (active ingredientin free base form) incorporated into each chewing piece of gum is suchthat the amount of active ingredient within each chewing piece from thatsource is 25 mg. As such, each chewing piece of the gum product (i.e.,each dosing unit) incorporates nicotine and a nicotinic compoundpurported to have selectivity to the α₇ nicotinic receptor subtype.

EXAMPLE 8

A coated gum generally similar in shape and form to anicotine-containing gum incorporating 4 mg of nicotine and commerciallyavailable as Zonnic (distributed by Niconovum AB, Sweden) is producedusing generally similar excipient ingredients and processing conditionsused for the manufacture of the commercial gum, except that the nicotineand microcrystalline cellulose thereof is replaced by a mixture ofnicotine/microcrystalline cellulose and a compound of AstraZeneca knownas AZD-3480. In one aspect, the amount of nicotine/microcrystallinecellulose incorporated into each chewing piece of gum is such that theamount of nicotine active ingredient within each chewing piece from thatsource is 3 mg; and the amount of AZD-3480 incorporated into eachchewing piece of gum is such that the amount of active ingredient withineach chewing piece from that source is 25 mg. In another aspect, theamount of nicotine/microcrystalline cellulose incorporated into eachchewing piece of gum is such that the amount of nicotine activeingredient within each chewing piece from that source is 3 mg; and theamount of AZD-3480 incorporated into each chewing piece of gum is suchthat the amount of active ingredient within each chewing piece from thatsource is 50 mg. As such, each chewing piece of the gum product (i.e.,each dosing unit) incorporates nicotine and a nicotinic compoundpurported to have selectivity to the α₄β₂ nicotinic receptor subtype.

EXAMPLE 9

A gum product generally similar in shape and form, and produced usinggenerally similar excipient ingredients and processing conditions, tothe nicotine-containing gum designated as Composition A as set forth inExample 6 of PCT WO 2007/104574 to Axelsson et al. is provided, exceptthat, in addition to the nicotine ingredient of each gum piece,sufficient compound of AstraZeneca known as AZD-3480 is incorporatedinto each gum piece such that the amount of active ingredient withineach dosage unit from that source is 25 mg. As such, each chewing pieceof the gum product (i.e., each dosing unit) incorporates nicotine and anicotinic compound purported to have selectivity to the α₄β₂ nicotinicreceptor subtype.

EXAMPLE 10

A gum product generally similar in shape and form, and produced usinggenerally similar excipient ingredients and processing conditions, tothe nicotine-containing gum designated as Composition B, as set forth inExample 6 of PCT WO 2007/104574 to Axelsson et al. is provided, exceptthat, in addition to the nicotine ingredient of each gum piece,sufficient compound of Targacept, Inc. known as TC-5619 is incorporatedinto each gum piece such that the amount of TC-5619 active ingredientwithin each gum piece is 25 mg. As such, each chewing piece of the gumproduct (i.e., each dosing unit) incorporates nicotine and a nicotiniccompound purported to have selectivity to the α₇ nicotinic receptorsubtype.

EXAMPLE 11

A lozenge generally similar in shape and form to a nicotine-containinglozenge incorporating 2.5 mg of nicotine is produced using generallysimilar excipient ingredients and processing conditions used for themanufacture of that lozenge set forth in Table 1 of Example 3 of PCT WO2007/104575 to Axelsson, except that, in addition to the nicotinebitartrate dihydrate ingredient of that lozenge, sufficient compound ofTargacept, Inc. known as TC-5619 is incorporated into each lozenge suchthat the amount of nicotine active ingredient within each lozenge is 2.5mg and the amount of TC-5619 active is 25 mg. As such, each lozenge(i.e., each dosing unit) incorporates nicotine and a nicotinic compoundpurported to have selectivity to the α₇ nicotinic receptor subtype.

EXAMPLE 12

A lozenge generally similar in shape and form to a nicotine-containinglozenge incorporating 2 mg of nicotine and commercially available asNiQuitin (distributed by GSK Consumer Healthcare NS) is produced usinggenerally similar excipient ingredients and processing conditions usedfor the manufacture of the commercial lozenge, except that the nicotinebitartrate active ingredient replaced by a mixture of nicotinebitartrate and a compound of Targacept, Inc. known as TC-5619. Theamount of nicotine bitartrate incorporated into each lozenge is suchthat the amount of nicotine active ingredient within each lozenge fromthat source is 2 mg; and the amount of TC-5619 incorporated into eachlozenge is such that the lozenge product incorporates 25 mg of TC-5619.As such, each lozenge (i.e., each dosing unit) incorporates nicotine anda nicotinic compound purported to have selectivity to the α₇ nicotinicreceptor subtype.

EXAMPLE 13

A pouch type of product similar in shape and form to anicotine-containing pouch commercially available as Zonnic (distributedby Niconovum A.B.) is produced using generally similar pouch material,excipient ingredients and processing conditions used for the manufactureof the commercial pouch, except that the nicotine/microcrystallinecellulose ingredient thereof is replaced by a mixture of a compoundknown as TC-5619 and nicotine/microcrystalline cellulose. The amount ofnicotine/microcrystalline cellulose incorporated into each pouch is suchthat the amount of nicotine active ingredient within each pouch fromthat source is the same as the commercially available pouch, and theamount of TC-5619 incorporated into the pouch is such that 25 mg ofTC-5619 active ingredient is incorporated into the pouch. As such, eachpouch (i.e., each dosing unit) incorporates nicotine and a nicotiniccompound purported to have selectivity to the α₇ nicotinic receptorsubtype.

EXAMPLE 14

Pouch type products generally similar in shape and form to anicotine-containing pouches set forth as snuff bag compositions E-J inExample 1 of PCT WO 2007/104573 to Axelsson et al. are produced usinggenerally similar excipient ingredients and processing conditions usedfor the manufacture of those pouch type products, except that 25 mg of acompound of AstraZeneca known as AZD-3480 also is incorporated withinthe formulation employed to manufacture that pouch product. Thus, bothnicotine and another nicotinic compound are active ingredientsincorporated into each dosage unit (i.e., within each pouch or bag). Assuch, each pouch (i.e., each dosing unit) incorporates nicotine and anicotinic compound purported to have selectivity to the α₄β₂ nicotinicreceptor subtype.

EXAMPLE 15

A spray formulation generally similar to a nicotine-containing sprayformulation designated as Composition A and set forth in Example 1 ofPCT WO 2006/100075 to Axelsson is prepared, except that, in addition,0.2 mg of varenicline active ingredient is incorporated into thatformulation. As such, the spray incorporates both nicotine and anicotinic compound purported to have selectivity to the α₄β₂ nicotinicreceptor subtype.

EXAMPLE 16

A spray formulation generally similar to a nicotine-containing sprayformulation commercially available as Zonnic (distributed by NiconovumA.B.) is prepared, except that, in addition, 10 mg of a compound ofAstraZeneca known as AZD-3480 is incorporated into that formulation.Thus, nicotine and another nicotinic compound are the active ingredientsincorporated into each dosage unit (i.e., within the spray formulation).As such, the spray incorporates both nicotine and a nicotinic compoundpurported to have selectivity to the α₄β₂ nicotinic receptor subtype.

A spray formulation generally similar to a nicotine-containing sprayformulation commercially available as Zonnic (distributed by NiconovumA.B.) is prepared, except that, in addition, 10 mg of a compound ofTargacept, Inc, known as TC-5619 is incorporated into that formulation.Thus, nicotine and another nicotinic compound are the active ingredientsincorporated into each dosage unit (i.e., within the spray formulation).As such, the spray incorporates both nicotine and a nicotinic compoundpurported to have selectivity to the α₇ nicotinic receptor subtype.

Those of skill in the art will appreciate that embodiments not expresslyillustrated herein may be practiced within the scope of the presentinvention, including that features described herein for differentembodiments may be combined with each other and/or with currently-knownor future-developed technologies while remaining within the scope of theclaims presented here. It is therefore intended that the foregoingdetailed description be regarded as illustrative rather than limiting.And, it should be understood that the following claims, including allequivalents, are intended to define the spirit and scope of thisinvention. Furthermore, the advantages described above are notnecessarily the only advantages of the invention, and it is notnecessarily expected that all of the described advantages will beachieved with every embodiment of the invention.

1. A nicotine-containing composition comprising: a source of nicotine;and an agonist or pharmaceutically acceptable salt thereof, havingselectivity to a receptor selected from the group consisting of an α₇nicotinic receptor subtype and an α₄β₂ nicotinic receptor subtype;wherein the composition is in a pharmaceutically acceptable form.
 2. Thecomposition of claim 1, wherein the receptor is an α₇ nicotinic receptorsubtype.
 3. The composition of claim 2, wherein the agonist is selectedfrom the group consisting ofN-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide,(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine,1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester,3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine,2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole,(5S)-spiro[1,3-oxazolidine-5,8′-1-azabicyclo[2.2.2]octane]-2-one,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide,5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide, EVP-6124,EVP-4473, TC-6987, and MEM3454.
 4. The composition of claim 3, whereinthe agonist isN-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide.5. The composition of claim 1, wherein the receptor is an α₄β₂ nicotinicreceptor subtype.
 6. The composition of claim 5, wherein the agonist isselected from the group consisting of7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine,(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine,[3-(2(S))-azetidinylmethoxy)pyridine]dihydrochloride,(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine,A-969933, S35836-1, S35678-1,3-(5,6-Dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptanes,AZD1446, and TC-6499.
 7. The composition of claim 6, wherein the agonistis selected from the group consisting of 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3) benzazepine and(2S,4E)-5-(5-isopropoxypyridin-3-yl)-N-methylpent-4-en-2-amine.
 8. Thecomposition of claim 1, wherein the source of nicotine is in the form ofa free base, a salt, a complex, or a solvate.
 9. The composition ofclaim 8, wherein the source of nicotine is nicotine polacrilex, nicotinefree base, nicotine tartrate or nicotine bitartrate.
 10. The compositionof claim 1, wherein the composition is in a form adapted for oralingestion.
 11. The composition of claim 10, wherein the pharmaceuticallyacceptable form is selected from the group consisting of a pill, tablet,lozenge, mini lozenge, capsule, caplet, pouch, gum and spray.
 12. Thecomposition of claim 1, wherein the source of nicotine is nicotinepolacrilex, nicotine free base, nicotine tartrate or nicotinebitartrate; wherein the receptor is an α₇ nicotinic receptor subtype;and wherein the pharmaceutically acceptable form is a gum, lozenge,pouch or spray.
 13. The composition of claim 1, wherein the source ofnicotine is nicotine polacrilex, nicotine free base, nicotine tartrateor nicotine bitartrate; wherein the receptor is an α₄β₂ nicotinicreceptor subtype; and wherein the pharmaceutically acceptable form is agum, lozenge, pouch or spray.
 14. A method for treating a condition,disease or disorder responsive to stimulation of nicotinicacetylcholinergic receptors, comprising orally or nasally administeringan effective amount of a pharmaceutical composition according to claim 1to a human subject.
 15. The method of claim 14, wherein saidadministering step comprises administering the pharmaceuticalcomposition to a human subject as a smoking cessation aid.
 16. Themethod of claim 14, wherein the receptor is an α₇ nicotinic receptorsubtype.
 17. The method of claim 14, wherein the receptor is an α₄β₂nicotinic receptor subtype.
 18. The method of claim 14, wherein thesource of nicotine is nicotine polacrilex, nicotine tartrate, ornicotine bitartrate.
 19. The method of claim 14, wherein one or both ofthe source of nicotine and the agonist are sorbed onto a porousparticulate carrier.
 20. The method of claim 19, wherein the porousparticulate carrier comprises microcrystalline cellulose.
 21. The methodof claim 14, wherein the composition is in a form adapted for oralingestion.
 22. The method of claim 21, wherein the composition is in theform of a gum, lozenge, tablet, spray or a pouch product.